Inhibitors are antibodies that the immune system develops because it sees the infused clotting factor as a foreign substance that needs to be destroyed. Antibodies are proteins that eat up the activated factor before it has time to stop the bleeding.
Who is at risk of inhibitor development?
Approximately 30% of people with severe hemophilia A are affected by inhibitors at some point in their lives. An inhibitor usually occurs between the 5th and 50th infusion of factor concentrate, but in rare cases can also be developed later in life.
While people with severe hemophilia are more likely to develop inhibitors, approximately 5-8% of people with mild or moderate hemophilia A develop inhibitors. The antibodies destroy not only the factor concentrate infused but also the small percentage of factor protein that the body was producing naturally. So, a person with mild or moderate hemophilia who develops an inhibitor now, in effect, has severe hemophilia (<1% circulating factor).
Approximately 2-3% of people with hemophilia B develop inhibitors. While inhibitors in people with hemophilia B are less common than hemophilia A, it can be even more challenging as about half of hemophilia B inhibitor patients will develop an anaphylactic reaction to infused factor IX, which can be life-threatening.
In addition to the type and severity of hemophilia someone has, there are other risk factors:
age/number of exposures to factor product
family history of an inhibitor
race/ethnicity (people of African American and Hispanic descent are at a higher risk of developing an inhibitor)
gene mutation (there are ongoing studies that indicate the type of genetic mutation one has may indicate a higher risk of inhibitor development)
intensive factor therapy related to surgery or trauma
The journal Haemophilia has published the results of a six-year study called the Hemophilia Inhibitor Research Study (HIRS) that was designed to test the feasibility of conducting national monitoring for inhibitors among people with hemophilia in the United States. In the study, investigators from 17 hemophilia treatment centers located across the United States enrolled 1,163 people with hemophilia and followed them for up to 6 years to learn the best way to determine who was at risk for developing an inhibitor. HIRS investigators and CDCresearchers found that people with hemophilia of all ages were at risk for developing an inhibitor and that unless people are regularly tested for an inhibitor, they can have one and not know it until it causes a severe bleeding problem.
What are the symptoms of an inhibitor?
Inhibitors destroy the infused factor concentrate, as well as the factor produced naturally by the body in people with mild and moderate hemophilia. A person who doesn’t have inhibitors will heal from injuries or feel better soon after the factor concentrate is infused. A person with an inhibitor does not get better after receiving a dose of factor that is appropriate for their weight.
How are inhibitors detected?
Children should be tested for inhibitors regularly, at least once per year. A blood test called activated partial thromboplastin time (APTT) is performed soon after factor concentrate is infused to calculate the time it takes for the person’s blood to clot. If clotting time is outside the range expected after an infusion, a second test called Bethesda assay is performed to confirm the diagnosis and to determine the level of inhibitor that the person has developed.
Inhibitor testing should be initiated if a patient is responding poorly to treatment. Some Hemophilia Treatment Centers (HTC) test more frequently in the early days of treatment and many test before every surgery and at annual comprehensive clinic visits.
Are inhibitors all the same?
No. Inhibitors come in different degrees of severity. Inhibitors are measured in titer (the amount of inhibitors present in a person’s blood) and immune response strength (how the immune system responds to additional infusions of factor concentrate).
Titer: The inhibitor titer is measured in Bethesda units (BU). This number represents the amount of inhibitors in the person’s body. Inhibitors are classified as follows:
Low Titer – Amount in the blood is less than 5 BU. The number, and therefore strength, of the inhibitor is low. People with low titer inhibitors can sometimes continue to use factor VIII or factor IX products to treat bleeds; they just need a lot more of it. Low titer inhibitors can sometimes resolve on their own.
High Titer – Amount of inhibitors found in the blood is greater than 5 BU. The number, and therefore strength of the inhibitor, is high. People with a high titer inhibitor get no benefit from factor VIII or factor IX, no matter how much they infuse.
Anamnestic Response: Once an inhibitor is present, the strength with which the body reacts to further exposure of factor concentrate, also called anamnestic response, can further classify the inhibitor type.
Low Responder – when people with low-responding inhibitors receive factor VIII or factor IX, the inhibitor titer does not rise. Because the titer stays low, they may be able to control bleeding by using larger quantities of those factor concentrates.
High Responder – when people with high-responding inhibitors are exposed to factor VIII or factor IX the immune system quickly triggers even more inhibitor development.
Treatment & Eradication of Inhibitors
Can inhibitors be eliminated?
Immune Tolerance Therapy
Yes. Immune tolerance therapy (ITT; also known as immune tolerance induction or ITI) is a treatment that consists of repeated infusions of factor concentrate over a period of time. The goal of ITT is to train the body to tolerate the factor concentrate and not react to the protein by creating antibodies.
ITT regimens vary in effectiveness and not one treatment has been proven to be more effective than another. Some treatments consist of daily doses of factor while other regimens recommend twice or three times per week. While it is generally agreed that inhibitor patients should begin ITT using the same factor product that resulted in the development of antibodies, some HTC’s may use a plasma-derived, von Willebrand containing factor product for ITT purposes.
Immune Tolerance is highly effective and works in about 80% of people with inhibitors. Predictors of success include how soon the inhibitor was detected and how soon ITT was started, and the peak level of inhibitor titer. Factor VIII patients have a higher rate of success than factor IX patients.
There are differing medical opinions on which ITT regimen or protocol is the most effective. Below is a brief discussion of ITT options; patients should discuss their individual medical treatment with their healthcare provider.
The Malmo Regimen is named for the area in Sweden where it was initiated in 1982. It is traditionally done over a short term (one-two months) in an in-patient hospital setting and is a combination of immune tolerance therapy with factor at high dose, immunosuppressive drugs and intravenous immunoglobulin (IVIG). Some have suggested that inhibitors are tolerized quickly using this method, but the side effects of the immunosuppressing drugs are a challenge. Few outside Scandinavia use this regimen.
The Bonn Protocol began in Bonn, Germany in the late 1970’s. It involves regular administration of factor replacement over a prolonged period of time in conjunction with the use of activated prothrombin complex concentrate (aPCC, brand name: FEIBA). Dosing rates vary and patients using this method traditionally stay on it for several months to several years.
INTERNATIONAL ITI STUDY & INTERNATIONAL WORKSHOP ON INHIBITORS: CONSENSUS RECOMMENDATIONS
In 2007, a group of leading hematologists issued recommendations. The findings can be found at the: “International workshop on immune tolerance induction: consensus recommendations”
A global study, published in 2011, examined the differences in the dosing of factor VIII at low and high doses for immune tolerance purposes. There did not appear to be a clear difference in the rate of ITT success between the high and low dose factor arms of the study, but it was reported that the high dose regimen meant toleration happened more quickly. The study did show a higher bleed rate for study participants on the lower dose regimen. The study was stopped because of this. The findings can be found at the: “The principal results of the International Immune Tolerance Study: a randomized dose comparison”.
When ITT Doesn’t Work/Decisions about when to stop ITT
According to the “International workshop on immune tolerance induction: consensus recommendations” the consensus definition of successful ITT involves three things:
The inhibitor titer can no longer be measured.
Factor recovery is greater than 66% of normal.
The half-life of Factor VIII is greater than 6 hours.
What happens if a patient tries ITT for a prolonged period and hasn’t met these criteria? The International ITI study states that if success has not come within 33 months of beginning ITT and a there is a lack of a 20% decrease in the inhibitor titer over a six month period, that it’s considered a failure. However, definitions of “failure” vary from one provider to another.
Some clinicians will begin “rescue therapy”, which may involve changing the dosing regimen of ITT or changing factor product.
OTHER INHIBITOR ERADICATION METHODS
While ITT is normally the first method of trying to eradicate an inhibitor, it does not always work for everyone. Other methods for inhibitor eradication are less studied and are somewhat controversial among medical professionals.
IMMUNOSUPPRESSION OR IMMUNOMODULATION
Immuno suppression is an act that reduces how the immune system activates or the efficacy of the immune system. In general, while this method has been used with limited success, it has not been thoroughly studied in congenital hemophilia inhibitor eradication and the long term effects of using immune suppressing drugs are unknown. Suppression can be against the entire immune system or focused specifically on the T or B cells. Various medications (immune suppressants) have been used, such as Rituximab (trade name Rituxan; Mycophenolate mofetil (trade name CellCept); Corticosteroids, i.e. Prednisone).
Treatment regimens vary from HTC to HTC.
Plasmapheresis is the removal, treatment, and return of (components of) blood plasma from blood circulation. This procedure will remove or reduce the antibodies that cause the inhibitor;, however, it does not have a lasting effect and is not a widely used method.
Bleeding Management of Inhibitors
Treating “bleeds” when inhibitors are present takes into account two things: the titer (the amount of inhibitors) and the anamnestic response (the strength) of the immune response. Some of the options available to treat bleeds in people with inhibitors include:
High doses of factor
Bleeds in “low responders” may be treated with higher doses of factor concentrate. This is not effective in people with high titer inhibitors because it is not feasible to infuse a large or frequent enough to overcome the strength of the inhibitor antibody.
To form a stable clot, multiple proteins must work together. These proteins are called “clotting factors” and they activate each other one after the other. The end result is fibrin, which forms a net to stabilize the clot. If one of the clotting factors is missing, the sequence is interrupted. That means you have a weak clot that will break apart because the fibrin net wasn’t formed to help hold it together. This process is called the coagulation cascade. (See here for a brief description of the coagulation cascade.) In short, factor VIII and factor IX eventually trigger the production of factor VIIa to continue the coagulation process and form a clot. Since people with inhibitors cannot replace the missing factor VIII or factor IX (because the antibodies destroy it), they must use a different product called bypassing agents. These products “bypass” the factors that are blocked by the inhibitor to continue the cascade and help form a clot.
Porcine factor VIII
The original plasma porcine factor VIII was made from pig plasma and was similar to the human factor VIII and was effective in treating bleeds in people with inhibitors. This product was discontinued in 2004. A new recombinant porcine factor VIII was approved for use in adults with acquired hemophilia A, but not congenital hemophilia A. This product has been used in congenital FVIII patients with inhibitors and found to be effective, but is not yet FDA-approved for this indication, although it has been accepted for publication.
Is Prophylaxis an Option for Those with Inhibitors?
Currently, one bypassing agent for those with inhibitors is FDA approved for prophylaxis. Concerns about prophylaxis for inhibitor patients include the cost of treatment, volume and length of infusion time, the short-half life, the burden of treatment, and the risk of thrombosis.
Challenges of Inhibitors
The need for good venous access is critical. Inhibitor patients may need frequent doses of bypassing agents to control bleeding. Those undergoing ITT need frequent needle sticks in order to deliver the factor. While peripheral vein infusion is the preferred method because it offers a potential reduction in infection risk and clots, it is often necessary for patients to look at other options because veins can be difficult to access or the frequency of dosing would be too difficult on peripheral veins. It is often necessary for patients to look at other venous access options.
Central Venous Access Devices (CVAD)
Central Venous Access Devices (CVADs) can be very helpful for patients (particularly children) who need repeated or urgent doses of factor. Many parents choose to have a CVAD placed in their child with a bleeding disorder simply for the freedom of being able to treat when needed at home rather than relying on a medical professional for each infusion. It does require a surgical procedure to place, and ultimately remove, a CVAD. There are some risks associated with CVADs: pneumothorax, hemothorax, bleeding, pain, infection.
Typically in hemophilia, a port is the preferred CVAD device. A port is a small disc shaped medical appliance inserted below the skin (most often in the chest area). It consists of a portal/reservoir compartment that is topped by a silicone bubble for needle insertion. This connects on the back side to a septum/plastic tubing. The septum in threaded surgically into a vein.
Patients and caregivers can be taught how to infuse and take care of a port at home. Ports can last for months to years. Patients can bathe and swim with a port.
Peripherally Inserted Central Catheter (PICC Line)
A peripherally inserted central catheter (PICC line) is typically inserted in the upper arm and is a long, slender, small and flexible tube. The tip of the catheter ends in a large vein in the upper chest. The end of the PICC line is external, meaning a small portion of the line hangs from the point of insertion on the arm. Patients and caregivers infuse through this point.
PICC lines are often a temporary solution for infusion necessity. They are helpful because each infusion does not require a needle stick, but bathing with a PICC line can be challenging and swimming is not allowed.
Tunneled Central Venous Access (Hickman or Broviac lines)
Hickman or Broviac lines are thin, long tubes made of silicone. A surgeon places or tunnels the line into one of the central veins that leads to the heart. The line hangs externally, (like a PICC line) and patients and/or caregivers can infuse through this point rather than a needle poke for each infusion. These lines can be more prone to infection because they are external and many parents report that bathing can be challenging.
Arterio-Venous Fistula (AVF)
A fistula is defined as an abnormal opening between body parts. In the case of an arterio-venous fistula (AVF), a surgeon creates a passageway or merge between an artery and vein, thereby allowing for an easier target vein to use for access. This most often is done in an arm or leg. This surgical procedure can allow for peripheral access of the AVF, but it takes time for the surgical site to heal and mature to a point of use. Advantages of an AVF include: can last for years, durable venous access, low risk of infection. Disadvantages include: visibility of AVF, maturation time after surgery, thrombosis and stenosis.
The physical toll on inhibitor patients can be very difficult due to the frequent bleeding episodes. Mobility can be limited and the use of assistive devices (wheelchairs, crutches, canes) may be needed. Many inhibitor patients develop joint damage. Pain management can be difficult. Surgical options do exist for inhibitor patients to relieve some orthopedic challenges. Inhibitor patients are encouraged to work closely with their HTC and physical therapist to determine what exercise and treatment options are best for them.
The costs associated with treating a person with inhibitors can be staggering because of the cost and amount of treatment needed to stop bleeding. In addition, people with inhibitors are more likely to be hospitalized due to a bleeding complication.
The effects of living with an inhibitor go beyond the physical and financial challenges. It takes an inordinate amount of time and effort for patients and caregivers to treat bleeds and the inhibitor. Frequent visits to the HTC, as well as emergency room and in-patient hospitalizations, can mean significant absences for school age children, and can create hardships in terms of employment. Pain issues can lead to feelings of anger, frustration and helplessness. Depression is one of the most common complications of chronic illness, and having an inhibitor can magnify some of those feelings. Limitations to mobility and independence can undermine confidence. Missing out on some of the everyday activities that others enjoy can lead to feelings of isolation. Families often have to dedicate large amounts of time to the patient and family relationships (siblings and spousal) can suffer. Both patients and caregivers report than interpersonal relationships are the best coping mechanism for the psycho-social challenges faced by living with an inhibitor.